ES2277857T3 - CHROME-HISTIDINE COMPLEXES AS NUTRITIONAL SUPPLEMENTS. - Google Patents

Abstract

Chromium is an essential element which has been shown to have beneficial effects on carbohydrate and lipid metabolism. Often, dietary intake is suboptimal, and nutritional supplements may not be effective due to poor absorption in the gastrointestinal tract. A novel chromium-histidine complex has been prepared which significantly improves absorption capability over current available chromium nutritional supplements. The complex is safe, easily prepared and may be combined with an ingestible carrier for consumption as a tablet, capsule, aqueous solution, food or food product.

Description

Chrome-histidine complexes As nutritional supplements.

Field of the Invention

Chromium, a physiologically important metal, It is an essential element necessary for the normal metabolism of Carbohydrates and lipids. Insufficient amounts may result in a malfunction of the metabolic process and lead to a series of physiological disorders. The membranes of absorptive cells of the mammalian intestine frequently they present a barrier to the effective absorption of chromium, leading to the presence of insufficient amounts in the blood flow. The The present invention relates to a chromium complex with improved absorption capacities.

Description of the prior art

The normal intake of chromium in the diet in the being Human and other mammals are often suboptimal. Intake insufficient dietary chromium leads to increases in risk factors associated with diabetes and diseases cardiovascular, including elevated insulin levels circulating, glucose, triglycerides, total cholesterol, reduced cholesterol-HDL levels and a function immunological disorder (Anderson, R.A., J. Am. Coll. Nutr. 17: 548-555,1998).

The beneficial effects of supplemental chromium in human subjects have been reviewed by Anderson ( supra ). There are more than 30 studies that report beneficial effects in subjects with varying degrees of glucose intolerance, from marginally elevated to apparent diabetes. Chromium supplementation has been shown to improve the signs and / or symptoms of diabetes in people with glucose intolerance (Cefalu et al ., J. Trace Elem. Exptl. Med., In press, 1999) and with diabetes type 1 (Ravina et al ., J. Trace Elem. Exptl. Med. 8: 183-190), type 2 (Ravina et al ., supra ; Anderson et al ., Diabetes 46: 1786-1791, 1997) , gestational (Jovanovic et al ., J. Trace Elem. Exptl. Med., in press, 1999) and steroid-induced (Ravina et al ., Diabetes Med. 16: 164-167, 1999; Ravina et al ., J Trace Elem. Exptl. Med., In press, 1999). Chromium also improves the functioning of insulin by increasing its binding to cells, the number of insulin receptors and the phosphorylation of insulin receptors, leading to increased insulin sensitivity. The amounts of supplemental chromium that have been shown to have beneficial effects in these studies were between 200 and 1,000 µg per day. In the study by Anderson et al. ( supra ), which involved 180 subjects with type 2 diabetes, the effects of chromium were greater at the dose of 1,000 µg per day than at the dose of 200 µg per day. The most drastic improvements were seen in hemoglobin A1C, which is a reliable indicator of long-term glucose control. Hemoglobin A1C in the placebo group was 8.5 ± 0.2%, 7.5 ± 0.2% in the 200 µg group and 6.6 ± 0.1% in the group of subjects who received 1,000 µg of chromium in the form of chromium picolinate per day for 4 months. The improvements in women with gestational diabetes were also greater in the group that received 8 µg per kg body weight per day compared to those who received 4 µg per kg body weight (Jovanic et al ., Supra ). Steroid-induced diabetes that could not be controlled with oral hypoglycemic medication and / or insulin also improved to acceptable levels in 47 of the 50 people who were given 600 µg of chromium in the form of chromium picolinate per day for 2 weeks, followed by a daily maintenance dose of chromium of 200 µg (Ravina et al ., Diabetes Med., supra ; Ravina et al ., J. Trace Elem. Exptl. Med., supra , 1999). Insulin sensitivity of obese subjects with a family history of diabetes also improved after 1,000 µg of supplemental chromium in the form of chromium picolinate (Cefalu et al ., Supra ).

It has also been shown that the levels of blood lipids improve after chromium supplementation, being the biggest improvements in total cholesterol, HDL cholesterol and triglycerides in subjects with higher initial levels.

In this way, it is clear that normal chromium food intake is often suboptimal and that beneficial effects can be observed after supplementation. The most widely used supplements are chromium picolinate and chromium polynicotinate. Chromium picolinate is currently the most widely used form, although it is not soluble in water, and questions about its toxicity have been raised (Sterns et al ., FASEB J. 9: 1643-1649, 1995). Chromium polynicotinate is a poorly absorbed mixture of several compounds; it is not stable and often forms insoluble oleated chromium polymers. The absorption of chromium from chromium chloride is generally approximately 0.4% (Anderson et al, J. Nutr . 113:. 308-311, 1983) and from chromium picolinate, currently chromium supplementation more usual, from approximately 1.2% to intakes of up to 1,000 µg per day (Campbell et al ., J. Appl. Physiol. 86: 29-30, 1999). The incorporation of chromium into rat tissues has been shown to vary widely depending on the way it is administered (Anderson et al ., J. Trace Elem. Exptl. Med. 9: 11-25, 1996). The highest concentrations were observed in the kidney, followed by liver, spleen, heart, lungs and gastrocnemius muscle. The remaining chromium compounds that are commercially available largely have not been tested for their biological activity and absorption. Additional forms of enhanced absorption chromium are urgently needed to help prevent and / or relieve signs, symptoms and other risk factors associated with diabetes and cardiovascular disease.

Summary of the Invention

The present inventors have discovered a new form of chromium that contains the amino acid histidine, which can obtained according to claim 1 and which unexpectedly presents better absorption than any compound containing chromium available under test. The complex must have little or no toxicity, other than that of chromium itself, which is very reduced Histidine, an essential amino acid, would result beneficial even at levels several times higher than those They would find in a nutritional supplement.

According to that discovery, it is a object of the invention to provide a complex of chromium-histidine that is useful as a supplement nutritional and that has an improved absorption capacity in comparison with chromium nutritional supplements available nowadays.

It is also an object of the invention provide a composition comprising the new complex of chromium-histidine and an ingestible carrier.

Other objectives and advantages will easily result evident from the following description.

Detailed description of the invention

More than three decades ago it was discovered that chromium was an essential nutrient, when rats fed a Torula yeast diet developed impaired glucose tolerance that was reversed with an insulin-enhancing factor whose active component was shown to it was trivalent chromium (Mertz and Schwarz, Am. J. Physiol. 196: 614-618, 1959; Schwarz and Mertz, Arch. Biochem. Biophys. 85: 292-295, 1959). Subsequently it has been established that the element is essential for fish, mice, marmosets, guinea pigs, pigs, cows and humans (Anderson, supra ). The nutritional need for chromium in humans was demonstrated during the 1970s, when a patient totally under parenteral nutrition developed severe signs of diabetes, including weight loss, glucose intolerance and peripheral neuropathy that were insulin refractory, but that improved with chromium supplementation (Jeejeebhoy et al ., Am. J. Clin. Nutr. 30: 531-538, 1977).

Although chromium as a food supplement is has been available for some time, the problems during administration apparently due to lack of absorption in the gastrointestinal tract. Without absorption adequate, the item cannot be distributed to those sites in the body that would use it effectively.

The amino acid-chromium complexes using other amino acids had been previously disclosed (Abdel-Monem, Patent No. 3,925,433, December 9, 1975; Ashmead et al ., Patent No. 4,863,989, September 5, 1989; Ridenour , patent No. 5,702,718, Dec. 30, 1997; Ashmead et al, No. 5,614,553 patent, March 25, 1997;.. Anderson et al, supra, 1996), however, no one has studied the relative effectiveness of chromium-histidine complexes in human absorption. Experiments have been carried out to investigate the efficacy of chromium-histidine complexes in the absorption process. Chromium was administered in the formulations indicated in Table 1 in doses of 200 µg of chromium, to three males and three adult females, and the absorption was measured during the first 24 hours based on the urinary excretion of chromium. The results are shown in Table 1, in which it can be seen that the new chromium-histidine complex is absorbed almost twice that of the nearest sample, chromium picolinate.

The complex can be obtained as described in Example 1. Complexing results in joining minus two histidine residues to the chromium metal ion, providing a structure of multiple rings. Can be formed bonds between the metal ion and both carboxyl and amino groups of the amino acid It is believed that, because histidine contains three Nitrogens (as electron donors), as well as a component annul, there is a possibility that several rings are formed heterocyclic, thus forming a multiplex unit.

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TABLE 1 Absorption of chromium compounds

one

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  \ begin {minipage} [t] {120mm} Chrome absorbed during the first
24 hours after ingestion of 200 µg of chromium in the various
indicated complexes, based on urinary excretion of chromium (3
males and 3 adult females). \ end {minipage} \ cr
 \ begin {minipage} [t] {120mm} ^ {a, b, c, d, e} Numbers with
different superscripts are significantly different with
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Institute, Cary,
NC). \ End {minipage} \ cr}
    

The compounds of chromium-histidine can be used for, although without limited to, improvements in glucose, insulin, cholesterol, HDL cholesterol, triglycerides and other factors of risk associated with diabetes and disease cardiovascular These compounds can also improve mass muscle and reduce body fat. Supplements surely they will be beneficial for humans as well as others mammals, such as farm animals and pets.

The estimated safe and adequate daily dietary intake (ESADDI) for chromium in children aged 7 to adults is 50 to 200 µg per day (National Research Council, recommended dietary allowance, 10th edition, Washington, DC: National Academy Press, 1989). Normal dietary intake of chromium for adults is suboptimal based on recommended intakes and studies that demonstrate the beneficial effects of chromium supplementation. The normal dietary intake of people in the United States is approximately 50% to 60% of the suggested minimum daily intake, of approximately 50 µg (Anderson et al ., 1991, in: Seventh International Symposium on Trace Elements in Man and Animals , Momcilovic, B., editor, Dubrovnik, pages 3 to 6).

Chromium-histidine complexes can be combined with any ingestible carrier for consumption as a tablet, capsule or as a fortifier in food or food products. Because the complex is water soluble and stable in aqueous solutions, various aqueous solutions can also be used effectively. Acceptable carriers are well known in the art, and these products can be prepared according to procedures well known to those skilled in the art. As a chromium supplement for humans, capsules, tablets, or the equivalent thereof, containing between about 100 µg and about 200 µg of chromium should be consumed once or twice a day between meals. The maximum beneficial effects of chromium are expected to occur at doses of approximately 400 µg of chromium in the form of a chromium-histidine complex a day or less. It should be noted that, because chromium is the essential nutrient of interest, effective amounts are administered in terms of chromium per se and not in terms of the total complex.

Examples Example 1 Synthesis of histidine complexes.

Slowly add a molar excess of three times from histidine to chromic acetate or chromium chloride in a aqueous solution at 80 ° C. Then the solution is heated for an additional 30 minutes, it cools to about room temperature, and the pH is adjusted to a pH between 5 and 5.5 with concentrated ammonium hydroxide. After cooling, the sample It can be lyophilized and used as a nutritional supplement. Too other amino acids may be included in the formulation, but should at least one molar equivalent of histidine present per mole of chromium.

Claims (5)

1. Composition comprising a complex of chromium-histidine in an amount effective for improve chromium adsorption in mammals, and a carrier ingestible, said complex being obtainable from chromium-histidine from chromic acetate or from Chromic chloride by adding to them in a solution aqueous at 80 ° C of a threefold molar excess of histidine, then heating for an additional 30 minutes, cooling up to about room temperature, and adjusting the pH up to a pH between 5 and 5.5 with concentrated ammonium hydroxide. 2. Composition according to claim 1, in the that said effective amount of chromium-histidine is between about 50 \ mug and about 1,000 \ mug of chrome. 3. Composition according to claim 2, in the that said effective amount of chromium-histidine is between about 100 \ mug and about 400 \ mug of chrome. 4. Composition according to claim 3, in the that said effective amount of chromium-histidine is between about 100 \ mug and about 200 \ mug of chrome. 5. Composition according to claim 1, in the that said composition is in the form of a tablet, a capsule, an aqueous solution, a food or a product food